Abstract
The activation of the transcription factor Nrf2 inhibits neuropathy and modulates the activity of delta-opioid receptors (DOR) in type 2 diabetic mice but the impact of Nrf2/HO-1 pathway on the antinociceptive actions of cannabinoid 2 receptors (CB2R) has not been assessed. Using male mice BKS.Cg-m+/+Leprdb/J (db/db) we investigated if treatment with cobalt protoporphyrin IX (CoPP), an HO-1 inductor, inhibited mechanical allodynia, hyperglycemia and obesity associated to type 2 diabetes. The antinociceptive effects of JWH-015 and JWH-133 (CB2R agonists) administered with and without CoPP or sulforaphane (SFN), a Nrf2 transcription factor activator, have been also evaluated. The expression of Nrf2, HO-1, NAD(P)H: quinone oxidoreductase 1 (NQO1) and c-Jun N-terminal kinase (JNK) in sciatic nerve and that of the CB2R on the dorsal root ganglia from animals treated with CoPP and/or SFN were assessed. CoPP treatment inhibited allodynia, hyperglycemia and body weight gain in db/db mice by enhancing HO-1/NQO1 levels and reducing JNK phosphorylation. Both CoPP and SFN improved the antiallodynic effects of JWH-015 and JWH-133 and expression of CB2R in db/db mice. Therefore, we concluded that the activation of antioxidant Nrf2/HO-1 pathway potentiate the effects of CB2R agonists and might be suitable for the treatment of painful neuropathy linked to type 2 diabetes.
Highlights
Diabetic neuropathy is a serious disorder associated with diabetes, which diminishes the quality of life [1]
Given that oxidative stress induced by hyperglycemia is a key factor for the progress of diabetic neuropathy and that heme oxygenase 1 (HO-1) triggered by the transcription factor Nrf2 potentiated the effects of delta-opioid receptors (DOR) in type 2 diabetic mice [20], we hypothesized that pre-treatment with cobalt protoporphyrin IX (CoPP) or sulforaphane (SFN), a Nrf2 transcription factor activator, might increase the analgesic efficacy produced by selective cannabinoid 2 receptors (CB2R) agonists in animals with type 2 diabetes
In BKS.Cg-m+/+Leprdb/J male mice which develop type 2 diabetes, with mechanical allodynia, hyperglycemia and obesity from 6-12 weeks of age [20,24,25], we investigated whether treatment with CoPP attenuated them through regulating the Nrf2, HO-1, NAD(P)H: quinone oxidoreductase 1 (NQO1) and Jun N-terminal kinase (JNK) protein levels in the sciatic nerve of these animals
Summary
Diabetic neuropathy is a serious disorder associated with diabetes, which diminishes the quality of life [1]. The activation of HO-1 caused powerful antinociceptive effects during acute, inflammatory, visceral and neuropathic pain [7,8,9,10], as well as in neuropathy related to type 1 diabetes [11], the influence of this enzyme on the inhibition of allodynia linked to type 2 diabetes has not evaluated. Given that oxidative stress induced by hyperglycemia is a key factor for the progress of diabetic neuropathy and that HO-1 triggered by the transcription factor Nrf potentiated the effects of delta-opioid receptors (DOR) in type 2 diabetic mice [20], we hypothesized that pre-treatment with CoPP or sulforaphane (SFN), a Nrf transcription factor activator, might increase the analgesic efficacy produced by selective CB2R agonists in animals with type 2 diabetes. The contribution of CoPP and SFN on the antiallodynic actions and expression of CB2R in the dorsal root ganglia from db/db mice were analyzed
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